Derivatives of flavone



United States Patent 3,410,851 DERIVATIVES OF FLAVONE Dale AdrianStauifer, Elkhart, Ind., assignor to Miles Laboratories, Inc., Elkhart,Ind., a corporation of Indiana No Drawing. Continuation-impart ofapplication Ser. No. 306,342, Sept. 3, 1963. This application Sept. 25,1967, Ser. No. 670,448

17 Claims. (Cl. 260-244) ABSTRACT OF THE DISCLOSURE A series of3-substituted flavones in which the substituent is an amino methylradical of the formula 1 CH2N/ where R and R may each be hydrogen, loweralkyl, aralkyl, arylhydroxyalkyl or pyridyl and may be a nitrogenheterocycle are useful as anti-convulsant, analgetic and bronchodilatoragents.

This application is a continuation-in-part of copending application Ser.No. 306,324 tiled Sept. 3, 1963, now abandoned.

This invention relates to novel derivatives of fiavone. In one of itsmore particular aspects this invention relates to basic derivatives offiavone.

The compounds of this invention may be described by means of thestructural formula wherein the radical represents a di-substituted aminoradical which may be open chain or cyclic. Where this radical is an openchain radical, R and R may each be hydrogen, lower alkyl, aralkyl,arylhydroxyalkyl or pyridyl and may vary inde pendently of one another,that is, R and R may be the same or different. Where the radical iscyclic then R and R taken together with the adjacent nitrogen may be anitrogen heterocycle, particularly a nitrogen rmonocyclic heterocyclicradical or a substituted derivative thereof. Of particular importanceare the phenyl substituted nitrogen monocyclic heterocyclic radicals andthose in which the substitution is with a pyridyl radical.

These compounds may exist in the form of their free bases as shown inthe above formula or may be furnished as Water soluble salts such as thehydrochloride or oxalate.

The compounds of this invention may be readily prepared, particularly bytwo convenient routes. In the first of these routeso-hydroxydibenzoylmethane is reacted with formaldehyde and an amine saltin a Mannich re- "ice action to give the corresponding salt of the basicflavone derivative desired. This route is exemplified in Equation 1.Although the reaction conditions are not critical, it is preferred toheat the reactants under reflux and to add an excess of formaldehyde inorder to assure complete reaction. The product, isolated as a saltcorresponding to the amine salt used, may be converted to the free baseor to various other salts by reaction with the appropriate acid.

Equation 1. 0

0H tBQ I HNR1R2 OHZO R I A CHz-N In another method of preparation of thecompounds of this invention the appropriate amine is reacted 'with 3-chloromethylflavone in accordance with Equation 2.

Equation 2:

The basic fiavone derivative may be recovered as the salt by using anappropriate acid. The product may also be isolated as the free base ifdesired.

The conditions of this reaction are not critical. It is necessary toheat the reaction mixture for varying times depending on the solventused. The reaction may be conducted in the absence of a solvent by usingan excess of the amine or in the presence of an appropriate solvent suchas toluene or a lower aliphatic alcohol. In the latter case a base suchas sodium carbonate is used to neutral ize the acid formed in thereaction.

The compounds of this invention are useful as anticonvulsant analgeticand bronchodilator agents.

Medications may be prepared including the novel compounds of thisinvention as active ingredients in the form of free bases orpharmacologically acceptable acid addition salts. Water soluble,pharmacologically acceptable, acid addition salts of the activeingredient are preferred. Suitable medications may be formulated bycombining at least one active ingredient With tillers, carriers,extenders and excipients generally used in pharmaceutical formulations.These medications are advantageously pre pared in solid or liquid statesas tablets, capsules, suspensions, solutions and similar dosage forms.The active in- Jgredient may be mixed with common diluents or tabletingadjuncts such as cellulose powder, cornstarch, lactose, talc, etc.according to accepted phanmaceutical manufacturing practices.

Medications including compounds of this invention as active ingredientsmay be effectively administered, intraperitoneally, subcutaneously, ororally. For example, a medication including 3-dimethylaminomethylfiavonehydrochloride in a saline solution was administered subcutaneously to agroup of mice. The analgesic properties of this active ingredient weredetermined substantially according to the artery clip method as setforth by Bianchi, C. and Franceschini, J., Brit. J. Pharmacol. 9:280,1954. An ED dose (median effective analgesic dose) of 15.6 =mg./kg. wasobserved.

In a similar manner, a medication including 3-(1-piperidylmethyl)-flavone hydrochloride in a saline solution was preparedand administered subcutaneously to a group of mice. The analgesicproperties of this compound were determined according to the artery clipmethod previously described and an ED dose of 47 mg/kg. was observed.

The specific medications described above were also used to determine anLD does (dose at which death occurs to 50% of animals treated). Themedications were administered intraperitoneally to a group of mice invarying doses. An LD dose of 68.1 ing/kg. was observed for 3-dimethylaminornethylflavone hydrochloride and an LD dose of 147 mg./kg.was observed for 3-(1-piperidylmethyl)flavone.

Although the hydrochloride form of these active ingredients were used todetermine ED and LD it will be understood by one skilled in the art thatother addition salts or the free base forms could also be used. Also, aperson skilled in the art will recognize that other active ingredientscould be utilized in dosages of similar magnitude.

The invention will be better understood by reference to the followingexamples which are intended for purposes of illustration and are not tobe construed as unduly limiting the invention except as the inventionmay be described in the claims appended hereto.

EXAMPLE 1 (A) 3-dimethylaminomethylflavone A mixture ofo-hydroxydibenzoylmethane (24.0 g., 0.1 mole), dimethylaminehydrochloride (9.0 g., 0.11 mole), 95% paraformaldehyde (4.7 g., 0.15mole), 25 ml. of 2- propanol and 5 drops of concentrated hydrochloricacid was heated under reflux for one (1) hour. Another 2.4 g. ofparaformaldehyde was rinsed into the clear solution with ml. of2-propanol, and the heating was continued for two (2) hours longer. Thesolvent was removed from the clear solution by distillation underreduced pressure. The syrup residue was shaken with 100 ml. of ether and200 ml. of water to which 10 ml. concentrated hydrochloric acid had beenadded. The aqueous layer was separated and treated with excess potassiumcarbonate. The free base was collected, washed with water andrecrystallized from aqueous ethanol. The beige colored crystals (15.5g., 56%) melted at 107-108.

Analysis.Calcd. for C H NO N(basic), 5.02; N(total), 5.02. Found:N(basic), 4.90; N(total), 5.11.

(B) 3-dimethylaminomethylflavone hydrochloride EXAMPLE 2 (A) 3-4-morpholinylmethyl) fiavone The procedure of Example 1 was carried outusing morpholine hydrochloride as the amine. The product was isolated ina yield of 52% and was found to have a melt ing point of 167 l68.

Analysis.--Calcd. for C H NO N(basic), 4.36; N(total), 4.36. Found:N(basic), 4.35; N(total), 4.35.

(B) 3-(4-morpholinylmethyl)flavone hydrochloride The procedure ofExample 1 was carried out to convert the free base to the hydrochloride.The yield of hydrochloride was quantitative with the hydrochloridehaving a melting point 242243.

Analysis.Calcd. for C H ClNO HCl, 10.19; N(basic), 3.90; N(total), 3.90.Found: HCl, 10.17; N(basic), 3.87; N(total), 3.89.

EXAMPLE 3 (A) 3-(l-piperidylmethyl)fiavone The procedure of Example 1was carried out as above 4 using piperidine hydrochloride. The productwas isolated in a yield of 38% with a melting point of 144-l45.

Analysis.Calcd. for C H NO N(basic), 4.39; N(total), 4.39. Found:N(basic), 4.37; N(total), 4.45.

(B) 3-(1-piperidylmethyl)flavone hydrochloride 4-phenyl piperidinehydrochloride. The product had a melting point of 252-253. (decomp.).

Analysis.Calcd. for C H ClNO HCl, 8.14; N(basic), 3.13; N(total), 3.13.Found: HCl, 8.01; N(basic), 3.07; N(total), 3.10.

EXAMPLE 5 (A) 3 -(1-hexamethyleneiminomethyl)flavone The procedure ofExample 1 was carried out as above using hexamethyleneiminhydrochloride. The product was isolated in a yield of 28% with a meltingpoint of 132-133.

Analysis.-Calcd. for C H NO N(basic), 4.20; N(total), 4.20. Found:N(basic), 4.16; N(total), 4.21.

(B) 3- 1-hexamethyleneiminomethyl fiavone hydrochloride This product wasprepared from the free base as in Example 1 in a yield of 88%. The saltwas found to have a melting point of 197198.

Analysis.-Calcd. for C H ClNO- HCl, N(basic), 3.79; N(total), 3.79.Found: HCl, N(basic), 3.71; N(total), 3.74.

EXAMPLE 6 (A) 3 -(6-methyl-6-phenyltetrahydro-1,3-oxazin- 3-ylmethyl)flavone The procedure of Example 1 was carried out as above using6-methyl 6 phenyltetrahydro-1,3-oxazin hydrochloride. The product wasisolated in a yield of with a melting point of 147148,

Analysis.-Calcd. for C H NO N(basic), 3.40; N(total), 3.40. Found;N(basic), 3.44; N(total), 3.48.

(B) 3-(6-methyl-6-phenyltetrahydro-1,3-oxazin- 3-ylniethyl)flavonehydrochloride.

This product was prepared from the free base as in Example 1 in a yieldof 82%. The product had a melting point of 202-203. (decomp.).

Analysis.-Calcd. for C H ClNO HCl, 8.14; N(basic), 3.13; N(total), 3.13.Found: HCl, 8.18; N(basic), 3.18; N(total), 3.10.

EXAMPLE 7 (A) 3-[4-(2-pyridyl)-l-piperazinylmethyl]fiavone The procedureof Example 1 was carried out as above described using4-(2-pyridyl)piperazine hydrochloride. The product was isolated in ayield of 46% with a melting point of l34135.

Analysis.Calcd. for C H N O N(basic), 7.05; N(total), 10.57. Found:N(basic), 7.00; N(total), 10.76.

(B) 3-[4-(2-pyridyl)-1-piperazinylmethyl]fiavone dihydrochloride Thisproduct was prepared from the free base as in Example l in a yield of97%. The salt was found to have a melting point of 255-256. (decomp.).

Analysis.-Calcd. for C H Cl N O HCl, 15.30; N(basic) (2), 5.96;N(total), 8.93. Found: HCl, 15.32; N(basic), 5.89; N(total), 8.95.

EXAMPLE 8 3-methylaminomethylflavone hydrochloride EXAMPLE 93-(4-morpho1inylmethyl)flavone 3-chloromethylflavone (7.6 g., 0.028mole) was mixed with 19.6 g. (0.112 mole) of morpholine. After the heatof the initial spontaneous exothermic reaction had dis sipated themixture was warmed gently. The solid material disappeared, and twoliquid layers formed. After heating under gentle reflux for five (5)minutes the mixture was cooled in an ice bath. The solid residue wasmixed with water, and an excess of hydrochloric acid was added. Thesolution was clarified with Nuchar C-lOOO-N, and excess potassiumcarbonate was added. The solid free base was collected, washed withwater and recrystallized from aqueous ethanol. The white needles (8.1g., 90%) melted at 167-168.

This is the same compound as in Example 2 above.

EXAMPLE 10 (A) 3 -(4-phenyl-l-piperazinylmethyl)fiavone A mixture of 3chloromethylflavone (13.5 g., 0.05 mole), phenylpiperazine (16.2 g., 0.1mole) and 50 ml. of toluene was heated under reflux for thirty (30)minutes. The mixture, which contained much undissolved solid material,was cooled and diluted with 200 ml. of ether. Then 300 ml. of water andan excess of hydrochloric acid was added. The mixture was shaken in aseparatory funnel, and the aqueous portion was withdrawn along with muchundissolved syrupy material. The aqueous mixture was diluted to 500 ml.with water and warmed until a clear solution formed. The solution wascooled, and some of the syrupy salt separated out again. The mixture wastreated with an excess of potassium carbonate. The solid free basecollected, washed with water and recrytsallized from aqueous ethanol.The hot solution was clarified with Nuchar C-1000-N. The beige coloredcrystals (15.8 g., 80%) melted at 148149.

Analysis.-Calcd. for C H N O N(basic) (1), 3.54; N(total), 7.07. Found:N(basic), 3.60; N(total), 7.15.

(B) 3-(4-phenyl-l-piperazinylmethyl)flavone hydrochloride The free base(15.3 g., 0.0386 mole) was mixed with a little 2-propanol, and 24.7 ml.of 1.566 N 2-propan0lic hydrogen chloride was added. This is thetheoretical quantity of acid required to form the hydrochloride salt.The mixture was concentrated by evaporation and diluted with hot ethylacetate. The beige colored crystals which formed on cooling werecollected, washed with ethyl acetate and dried. The product (13.2 g.,79%) melted at 201-202 (decomp.).

Analysis. Calcd. for C25H25C1N2021 N(basic) 6.47; N(total), 6.47. Found:HCl, 8.43; N(basic), 6.47; N(total), 6.42.

EXAMPLE 11 (A) 3-[4-(3-chlorophenyl)-l-piperazinylmethyl]flavone Theprocedure of Example 10 was carried out using mchlorophenylpiperazine.The product was isolated in a yield of 52% with a melting point of155156.

6 Analysis.-Calcd. for C H ClN 0 N(basic) (1), 3.25; N(total), 6.50.Found: N(basic), 3.26; N(total), 6.68.

(B) 3- [4- 3-chlorophenyl)- l-piperaziinylmethyl] flavone oxalate Theoxalate was prepared as in Example 10 above using oxalic acid instead ofhydrochloric acid. The salt was isolated in a yield of 88% with amelting point of 174- 175. (decomp.).

Analysis. Calcd. for C H ClN O Z N.E., N(basic), 2.69; N(total), 5.38.Found: N.E., 263.2; N(basic), 2.62; N(total), 5.41.

EXAMPLE 12 (A) N- (Z-pyridyl) -N- 2-hydroxy-2-phenylethyl) -3-aminomethylflavone The procedure of Example 10 was carried out using N-(2 pyridyl)-B-hydroxyphenethylamine. The product was isolated in a yieldof 12% with a melting point of 137- 138.

Analysis.Calcd. for C H N O N(basic) (1), 3.12. Found: N(basic), 3.14.

(B) N-(Z-pyridyl)-N-(2-hydroxy-2-phenylethyl)-3- aminomethylflavonehydrochloride This product was prepared from the free base as in Example10 in a yield of 95%. The salt was found to have a melting point of192193.

Analysis. Calcd. for C H ClN O HCl, 7.52; N(basic) (1), 2.89; N(total),5.78. Found: HCl, 7.46; N(basic), 2.95; N(total), 5.77.

EXAMPLE 13 (A) 3-diethylaminomethylflavone The procedure of Example 10was carried out using diethylamine. The product was isolated in a yieldof 92% with a melting point of 84-85 Analysis. Calcd. for C H NON(basic), 4.56; N(total), 4.56. Found: N(basic), 4.62; N(total), 4.59.

(B) 3-diethylaminomethylflavone hydrochloride This product was preparedfrom the free base as in Example 10 in a yield of The salt was found tohave a melting point of 201-202.

Analysis.-Calcd. for C H CINO HCl, 10.60; N(basic), 4.07; N(total),4.07. Found: HCl, 10.68; N(basic), 4.20; N(total), 4.13.

EXAMPLE 14 3-benzylaminomethylfiavone hydrochloride This product wasprepared in accordance with the procedure of Example 10 in a yield of61% using benzylamine. The product had a melting point of 245-246.

Analysis.-Calcd. for C H ClNO HCl, 9.65; N(basic), 3.71; N(total), 3.71.Found: HCl, 9.60.; N(basic), 3.68; N(total), 3.71.

EXAMPLE 15 3-(n-butylaminomethyl)flavone hydrochloride This product wasprepared in accordance with the procedure of Example 10 in a yield of27% using n-butylamine. The product had a melting point of 243244.

Analysis.-Calcd. for C H ClNO HCl, 10.61; N(basic), 4.07; N(total),4.07. Found: HCl, 10.67; N(basic), 4.06; N(total), 4.07.

EXAMPLE 16 3- [4-(3-chlorophenyl) -1-piperazinylmethyl]flavone A mixtureof 3-chloromethylflavone (13.5 g., 0.05 mole),1-(3-chlorophenyl)piperazine (9.8 g., 0.05 mole), sodium carbonate (5.3g., 0.05 mole) and 50 ml. of ethanol was heated under reflux for two (2)hours. The mixture was diluted with water, and an excess of hydrochloricacid was added. A small quantity of undissolved solid material wasremoved by filtration, and excess potassium carbonate was added. Thesolid free base was collected, washed with water and recrystallized fromaqueous ethanol. The almost white crystals (14.4 g., 67%) melted at155l56.

This is the same compound as in Example 11 above.

EXAMPLE 17 N-(2-pyridyl)-N- (Z-hydroxy-Z-phenylethyl 3-aminomethylfiavone This compound was prepared in accordance with themethod of Example 16 using N (2-pyridy1)-B-hydroxyphenethylamine. Theproduct was isolated in a yield of 15% with a melting point of l37138.

This compound is the same as in Example 12 above.

In summary, this invention provides a series of novel fiavonederivatives which are useful as anti-convulsant, analgetic andbronchodilator agents.

What is claimed is:

1. A compound selected from the group consisting of compounds of theformula wherein R and R each independently is a member selected from thegroup consisting of hydrogen, lower alkyl, phenyl lower alkyl, phenylhydroxy lower allkyl and pyridyl, and R and R taken together withnitrogen in the radical is a member selected from the group consistingof 4-hydroxy-4-phenyl-l-piperidyl, 6-methyl6-phenyltetrahydro-l,3-oxazin-3-yl, l-hexamethyleneimino, 4-(2-pyridy1)-l-piperazinyl, l-piperidyl, 4-phenyl l-piperazinyl, 4-(3-chlorophenyl)-1\-piperazinyl, 4-morpholinyl, and pharmacologicallyacceptable salts thereof.

2. A compound according to claim 1 which is3-dimethylamino-methylflavone.

3. A compound according to claim 1 which is 3-(4-hydroxy-4-phenyl-1-piperidylmethyl)flavone.

4. A compound according to claim 1 which is 3-(6- methyl-6phenyltetrahydro 1,3-oxazin 3 ylmethyl)- flavone.

5. A compound according to claim 1 which is 3-(1-hexamethyleneiminomethyl)flavone.

6. A compound according to claim 1 which is 3-[4-(2-pyridyl)-l-piperazinylmethyl]flavone.

7. A compound according to claim 1 which is 3-(1-piperidylmethyl)flavone.

8. A compound according to claim 1 which is 3-(4-phenyl-1-piperazinylmethyl)flavone.

9. A compound according to claim 1 which is 3-[4-(3- chlorophenyl)-1-piperazinylmethyl] flavone.

10. A compound according to claim 1 which is N-(Z- pyridyl)N-(2-hydroxy-2-phenylethyl)-3-aminomethylflavone.

11. A compound according to claim 1 which is 3-benzylaminomethylflavone.

12. A compound according to claim 1 which is 3-(4-morpholinylmethyl)flavone.

13. A compound according to claim 1 which is3-diethylaminomethylflavone.

14. A compound according to claim 1 which is3-(nbutylaminomethyl)flavone.

15. A compound according to claim 1 which is 3-methylaminomethylflavone.

16. A process for the preparation of a compound of claim 1 of theformula wherein R and R each independently is a member selected from thegroup consisting of hydrogen, lower alkyl, phenyl lower alkyl, phenylhydroxy lower alkyl and pyridyl, and R and R taken together withnitrogen in the radical is a member selected from the group consistingof 4- hydroxy-4-phenyl-l-piperidyl, 6-methyl 6-phenyltetrahydro-1,3oxazin-3-yl, 1 hexamethyleneimino, 4-(2- pyridyl) l-piperazinyl, lpiperidyl, 4-phenyl-1-piperazinyl, 4 (3-chlorophenyl)-1-piperazinyl,4-morpholinyl, which comprises reacting o-hydroxydibenzoylmethane withformaldehyde and a salt of a secondary amine of the formula wherein R Rand each has the same significance as above.

17. A process for the preparation of a compound of claim 1 of theformula wherein R and R each independently is a member selected from thegroup consisting of hydrogen, lower alkyl, phenyl lower alkyl, phenylhydroxy lower alkyl and pyridyl, and R and R taken together withnitrogen in the radical is a member selected from the group consistingof 4- hydroxy-4 phenyl l-piperidyl, 6-methyl6-phenyltetrahydro-1,3-oxazin-3-yl, l-hexamethyleneimino,4-(2-pyridyl)-l-piperazinyl, l-piperidyl, 4-phenyl 1- piperazinyl, 4- 3-chlorophenyl) -1-piperazinyl, 4-morpholinyl, which comprises reacting3-cholormethylfiavone with a secondary amine of the formula 9 10 whereinR R and References Cited R1 Wiley: I. Am. Chem. Soc, vol. 74, pp. 4326-81952 R2 5 HENRY R. JILES, Primary Examiner.

each has the same significance as above. R. T. BOND, Assistant Examiner.

